As is well known in the art, degradation of a cell can, and in many instances will, result in degradation or impairment in the physical structure and/or function of the organ associated therewith. By way of example, it is well established that degradation and death of cells can, and in many instances will, result in cardiovascular dysfunction and disease, e.g. congestive heart failure, liver dysfunction and disease, and various cancers, e.g. basal and squamous cell carcinomas, adenocarcinoma, etc.
Referring to FIG. 1, the cell cycle consists of four distinct phases: the G1 phase, S phase (synthesis) and G2 phase (collectively known as the interphase), and the M phase (mitosis). Activation of each phase is dependent on the proper progression and completion of the previous phase.
As discussed in detail below, the M phase is itself composed of two tightly coupled processes: mitosis, in which the cell's chromosomes are divided between the two sister cells, and cytokinesis, in which the cell's cytoplasm divides in half to form distinct cells.
After cell division, each of the daughter cells begins the interphase of a new cycle. Although the various stages of interphase are not usually morphologically distinguishable, each phase of the cell cycle has a distinct set of specialized biochemical processes that prepare the cell for initiation of cell division.
The first phase within interphase, i.e. from the end of the previous M phase until the beginning of DNA synthesis, is called the G1 phase or gap. It is also referred to as the growth phase.
During this phase, the biosynthetic activities of the cell, which had been considerably slowed down during the M phase, resume at a high rate. The duration of the G1 phase is highly variable, even among different cells of the same species.
The ensuing S phase commences when DNA synthesis commences; when it is complete, all of the chromosomes have been replicated, i.e. each chromosome has two (sister) chromatids. Thus, during this phase, the amount of DNA in the cell has effectively doubled, although the ploidy of the cell remains the same.
The ensuing G2 phase lasts until the cell enters the M phase (or mitosis). Significant biosynthesis similarly occurs during this phase. The biosynthesis mainly involves the production and subsequent lengthening of microtubules, which are required during the process of mitosis.
The relatively brief M (or Mitotic) phase consists of two tightly coupled processes: mitosis, in which the cell's chromosomes are divided between the two sister cells, and cytokinesis, in which the cell's cytoplasm divides in half to form distinct cells; the noted nuclear division(s) often referred to as karyokinesis. The M phase is typically broken down into several distinct phases, sequentially known as prophase, prometaphase, metaphase, anaphase, and telophase.
When a cell has temporarily or reversibly stopped dividing or regenerating it is often deemed to have entered a quiescent or senescent state referred to as the G0 phase.
Non-proliferative cells generally enter the senescent G0 phase or state from the G1 phase and may remain senescent for long periods of time, possibly indefinitely (as is often the case for neurons). This is very common for cells that are fully differentiated.
Cellular senescence was first described by Hayflick and Moorhead (1961) when they observed that normal human fibroblasts entered a state of irreversible growth arrest after serial passage in vitro. In contrast, abnormal cells, such as cancer cells, did not enter this growth arrested state and proliferated indefinitely.
The maximum number of cell divisions that a cell can undergo, termed the Hayflick limit, varies from cell type to cell type and organism. In fibroblasts, this number is about 50 divisions, after which cell division ceases.
However, some cells become senescent after fewer replication cycles as a result of DNA damage or degradation, e.g., DNA mutations, DNA oxidation and chromosome losses, which would make a cell's progeny nonviable. If the DNA damage cannot be easily repaired, the cells either age or self-destruct (i.e. apoptosis or programmed cell death).
The process of cellular senescence can also be triggered by several additional mechanisms, including telomere shortening (i.e. a form of DNA damage or degradation).
Telomeres consist of repetitive DNA elements at the end of linear chromosomes that protect chromosome ends from degradation and recombination. Due to DNA replication mechanisms and oxidative stress, telomeres become progressively shorter with each round of replication. As increasing numbers of cell division occur, the telomeres reach a critically short length, which present as double-stranded DNA breaks, resulting in telomere-initiated senescence.
The ability to modulate oxidative stress and, thereby, telomerase activity and mitochondria function, thus provides the opportunity to extend the lifespan of a living cell and, by extension the organ, tissue or entire organism associated therewith.
It is therefore an object of the present invention to provide compositions and methods to modulate oxidative stress and, thereby, telomerase activity and mitochondria function, whereby the lifespan of a living cell and, by extension the organ, tissue or entire organism associated therewith can be extended.